Sudden cardiac death syndrome, following coronary occlusion and acute myocardial ischemia, is a leading cause of mortality in adults in the U.S. During the first 24 hours of ischemia, the infarct zone slowly expands in the territory of the occluded artery, and serious cardiac arrhythmias leading to death can occur. These arrhythmias probably are caused by (a) "low potential automaticity" that occurs in "endocardial border zone" Purkinje fibers with maximum diastolic potentials < or = - 60 mV, or (b) triggered activity in ventricular muscle cells on the epicardial or lateral borders of the infarct. Here, we will study the pharmacology of models of this low potential automaticity and triggering using standard microelectrode techniques. We will also study the effects of antiarrhythmic drugs on catecholamine-enhanced automaticity occurring at both the high and low levels of maximum diastolic potential (i.e., about - 90 mV and -55 mV, respectively). Such catecholamine- enhanced automaticity must also contribute to the infarct arrhythmias. These studies should help to explain the effects of antiarrhythmic drugs on tachycardias associated with myocardial infarction, and may explain why some tachycardias are resistant to drug therapy. We will also carry out experiments using current clamp techniques to characterize the voltage dependence of drug effects on high potential automaticity (which occurs from maximum diastolic potentials > -80 mV), intermediate potential automaticity (which occurs from maximum diastolic potentials of -61 to -70 mV) and low potential automaticity in barium- or cesium- pretreated Purkinje fibers. Finally, we will also use enzymatically- isolated single Purkinje cells and Purkinje cell clusters to investigate fluctuations of cleft K+ concentration ([K+]c), and or intracellular Ca++ activity ([CA++]i), during automaticity. These single cell/cell cluster experiments should permit us to determine whether time-dependent decreases of g R, sufficient to explain phase 4 depolarization, occur as a consequence of progressive declines of [K+]c and [Ca++]i during diastole.